Project Abstract Sulfonamides, sulfamides, and sulfamates are incredibly important compounds with therapeutic applications against cancer, HIV, and microbial infections. Existing strategies to make these nitrogen-based sulfur(VI) compounds are limited by the commercial availability of starting materials and harsh reactions preventing late-stage functionalization. Sulfur-fluoride exchange (SuFEx) chemistry is a promising new pathway to synthesize sulfonylated products from sulfur(VI) fluorides and nucleophiles. However, the stability of sulfur(VI) fluorides compared to other halogen analogues present challenges for synthetic applications. Herein, we propose the development of new sulfur-fluoride exchange (SuFEx) reactions to synthesize nitrogen-based sulfonylated compounds by activating sulfur(VI) fluorides with metal-based Lewis acidic salts and organocatalysts. The proposed work is innovative because it seeks to develop attractive alternatives toward introducing sulfonylated moieties into organic compounds by employing easy to handle starting materials, cheap Lewis acid salts and organic-based catalysts. Successful implementation of the research proposed herein will lead to novel one-step SuFEx transformations toward S?N and S?O formation enabling the development of new, diverse libraries for drug discovery. The first aim focuses on the development of calcium-mediated activation of sulfamoyl fluorides and fluorosulfates to make sulfamides and sulfamates ? a critically underdeveloped class of sulfonylated compounds. This transformation will represent a considerable advance over current methods that rely on starting materials that are challenging to synthesize or isolate. The second aim seeks to understand the mechanism of Lewis-acid activation of sulfur(VI) fluorides in SuFEx chemistry. Information gleaned from these kinetic and computational studies will provide critical information towards understanding key intermolecular interactions that govern the reaction, leading to new generation of SuFEx reactions. The third aim will focus on the development of catalytic SuFEx reactions using Lewis acidic salts and basic organocatalysts; establishing new modes to activate sulfur(VI) fluorides toward sulfonylated compounds. The PI?s research has enhanced the research environment at Pomona College by engaging undergraduate students in organometallic catalysis and synthetic research. The work in this proposal will expose undergraduates to biomedically-relevant research with significant impact in synthesis and medicinal chemistry.